Table 4.
Other classes of phosphatase modulator
| Compound (company/investigator) | Target | IC50 | Stage of development | Comments | Refs. |
|---|---|---|---|---|---|
| Protein–protein interaction modulators | |||||
| Cyclosporine (CsA) (Sandoz (now Novartis)) | Calcineurin |
CsA–CypA Ki = 675 nM |
FDA approved | Immunosuppressant for prevention of organ transplant rejection and treatment of some autoimmune disorders; binds to immunophilin CypA; CsA–CypA complex competitively inhibits calcineurin | 15,230 |
| Tacrolimus/FK506 (Fujisawa Pharmaceuticals) | Calcineurin |
FK506–FKBP Ki = 14 nM |
FDA approved | Immunosuppressant for prevention of organ transplant rejection and treatment of atopic dermatitis; binds to immunophilin FKBP; FK506–FKBP complex inhibits calcineurin competitively | 15,230 |
| Pimecrolimus (Novartis) | Calcineurin |
FK506–FKBP Ki = 117 nM |
FDA approved | Topical calcineurin inhibitor for atopic dermatitis; inhibits calcineurin as complex with FKBP | 15,231 |
| Voclosporin (Isotechnika/Aurinia Pharmaceuticals) | Calcineurin | NR | FDA approved | FDA approved in 2021 for lupus nephritis in combination with immunosuppressive therapy; CsA analogue | 15,16,232 |
| NCGC00378430 (Zhao (University of Colorado)/Ford (University of Colorado)/Marugan (NIH NCATS) Laboratories) | EYA2−SIX1 | 52 μM | Tool compound | Inhibits interaction between EYA2 and SIX1; orthotopic mammary fat pad NCGC00378430 administration decreases tumour metastasis, although some animals develop hepatocyte necrosis | 233 |
| PSP regulatory subunit inhibitors | |||||
| Sephin1 (Bertolotti Laboratory, Medical Research Council Laboratory of Molecular Biology) | PP1–GADD34 | NR | Tool compound | Derivative of guanabenz, with reduced α2-adrenergic agonist effects; efficacious in mouse models of MS | 55,234,235 |
| Raphin1 (Bertolotti Laboratory, Medical Research Council Laboratory of Molecular Biology) | PP1–R15B | NR | Tool compound | Orally administered raphin1 crosses the blood–brain-barrier without adverse effects on mouse weight, liver function, pancreatic function or memory, and reduces huntingtin protein aggregates in a model of Huntington disease | 236 |
| PSP holoenzyme activatiors | |||||
|
Fingolimod/FTY720, CC11 and CM-1231 (Novartis (FTY720), Trentin Laboratory (CC11; Venetian Institute of Molecular Medicine, Centro di Eccellenza per la Ricerca Biomedica Avanzata and University of Padua) and Odero Laboratory (CM-1231; University of Navarra)) |
B56γ-containing PP2A heterotrimer | NR | FDA approved (fingolimod/FTY720) | Sphingosine analogues with PP2A-mediated antitumour activity; FTY720 is an anti-inflammatory drug FDA approved in 2010 for MS; phosphorylation of FTY720 by sphingosine kinase mediates most anti-inflammatory effects; non-phosphorylated FTY720 binds SET and activates B56γ-containing PP2A by inhibiting SET’s association with PP2A-C; C11 and CM-1231 are non-phosphorylatable analogues | 151,152,237–242 |
| DT-061 (Narla (University of Michigan) and Ohlmeyer (Mount Sinai) Laboratories) | PPP2R1A, PPP2CA and PPP2R5A/B56α-containing PP2A heterotrimer | NR | Tool compound | Oral DT-061 administration in mice inhibits growth of xenografted H358 KRAS mutant lung adenocarcinoma and transgenic KRAS-LA2 lung tumours | 154,155,243 |
| Biologics | |||||
| PRL3-zumab (Zeng Laboratory, National University of Singapore) | PRL3 | NR | Phase II trial | Targets PRL3 expressed on the outer surface of tumours; suppresses PRL3+ but not PRL3− gastric and liver tumours in orthotopic mouse models | 244,245 |
| ARP-1536 (Aerpio Therapeutics) | VE-PTP | NR | Preclinical | Binds to the VE-PTP extracellular domain; exhibits biological activity similar to VE-PTP inhibitor AKB-9778 in preclinical experiments when administered intravitreally | 28 |
| RPTPσ decoy protein (Bottini Laboratory, La Jolla Institute for Allergy and Immunology) | RPTPσ | NR | Preclinical | Activates RPTPσ by releasing it from binding to extracellular matrix proteoglycans; intravenous administration attenuates arthritis in mice | 56,57 |
| Intracellular RPTPσ-targeting peptide (Silver Laboratory, Case Western Reserve University) | RPTPσ | NR | Tool compound | Mimics intracellular juxtamembrane ‘wedge’ motif; promotes innervation and functional restoration in mice following spinal cord injury and cardiac innervation in myocardial infarction model; enhances remyelination in MS models | 246–248 |
CypA, cyclophilin A; EYA, eyes absent; FKBP, FK506-binding protein; IC50, half-maximal inhibitory concentration; Ki, inhibition constant; MS, multiple sclerosis; NR, not reported; PRL3, phosphatase of regenerating liver 3; PSP, protein serine/threonine phosphatase; RPTP, receptor PTP; SET, su(var)3-9, enhancer of zeste, trithorax; SIX1, sine oculis homeobox homologue 1; VE-PTP, vascular endothelial PTP.